The proceedings have been published in the Journal of Inherited Metabolic Disease     Volume 32 No 3 June 2009



First Annual Symposium on Pediatric Neurotransmitter
Diseases May 18 to 19, 2002 Annals of Neurology Vol 54 Supplement 6 2003 For a free copy of the Journal
[email protected]


What is Tyrosine Hydroxylase Deficiency?


Tyrosine Hydroxylase (TH) deficiency (also known as Recessive Dopa-

Responsive Dystonia) is a rare metabolic disorder characterized by the

lack of the enzyme involved in converting the amino acid tyrosine to Ldopa.

TH is a critical enzyme in normal dopamine production. Lack of

this enzyme means neurotransmitters are blocked from signaling one

another appropriately. The neurotransmitters dopamine, norepinepherine,

epinepherine (collectively known as catecholamines) and serotinin are

deficient in the central nervous system and periphery.


Patients with TH Deficiency can develop movement disorders, autonomic symptoms (blood pressure instability, temperature irregularities), abnormal eye movements and neurological impairment.


What symptoms are associated with TH Deficiency?


A wide range of symptoms can be associated with TH Deficiency, and

involvement can vary from mild, moderate to severe.


Mild:  In the mildest cases, walking or running may be clumsy but little

else may be noticed initially.  Symptoms may progress slowly as the

child gets older. One side of the body may seem weaker, or the child

may begin to walk up on their tiptoes due to some tightness of the leg

muscles. Attention difficulties in school are common. Children with mild

symptoms are often treated successfully with medication.


Moderate:  In moderately affected cases, the child may not be able to

walk at all, or walking may be extremely difficult. Unusual arm posturing

or positions of their arms with attempts to walk or walk on their toes is

common. Abnormal eye movements, tremor and speech delay may be

present. Children with moderate symptoms often respond well to treatment

but full benefit may take many months.


Severe:  In the most severe cases children are physically disabled and

affected from early infancy. This is sometimes known as the Infantile

Parkinson’s disease variant. Patients may demonstrate all or some of

the following symptoms;


Muscle tightness (rigidity, spasticity)

Abnormal posturing (arching of the back)


Poor muscle control

Abnormal eye movements (eye deviation upward, downward or towards

the nose)

Strabismus (cross-eyed)

Ptosis (droopiness of the eyelids)

Speech delay


Difficulties feeding or swallowing


Torticollis (involuntary deviation of the head and neck)

Intermittent color changes

Unexplained low body temperatures or fevers

Low blood sugar

Difficulty regulating blood pressure

Children who are severely affected are more difficult to treat, and several

medications may be needed. They are unusually vulnerable to side

effects of the medications, which can result in excessive movement

and irritability. Response may be slow, with some continued benefit over

months to years, but may not result in the complete resolution of all

symptoms. Symptoms may present or worsen during other illnesses

the child might experience.

Children with TH Deficiency are often considered clumsy or uncoordinated

and are often initially diagnosed with cerebral palsy.


What causes TH Deficiency?


TH Deficiency is inherited as an autosomal recessive trait. In recessive

disorders, the condition does not occur unless an individual inherits the

same defective gene for the same trait from each parent. A child who

receives one normal gene and one gene for the disease will be a carrier

but usually will not show symptoms. The risk of transmitting the disease

to the children of a couple, both of whom are carriers for a recessive

disorder is 25%. The risk is the same for each pregnancy.



Who gets TH Deficiency?


It is unclear at present whether males or females are affected any differently.

Only a few dozen cases have been identified to date worldwide as

of 2003. It is suspected that many cases either go unrecognized or




How is TH Deficiency diagnosed?


A diagnosis of TH Deficiency is based upon a two stage testing procedure:



A lumbar puncture (spinal tap) to determine abnormalities of neurotransmitter



Note: Testing for PND’s is not a routine procedure and requires

specific guidelines. Should the treating physician or consultant

require more information on laboratories please refer to the Pediatric

Neurotransmitter Disease Association at  www.pndassoc.org

or contact:

Keith Hyland PhD
Medical Neurogenetics, LLC
Atlanta, GA.
Phone (678) 225-0222
Fax (678) 225-0212
[email protected]
[email protected]


Teodoro Bottiglieri, PhD
Principle Investigator, Director of Neuropharmacology
Adjunct Professor of Biomedical Studies
Baylor University Medical Center
Institute of Metabolic Disease
Phone (214) 820 4748
Fax (214) 820 4853
Web: http://www.baylorhealth.edu/imd/
[email protected]




Once the diagnosis is suspected on the basis of cerebrospinal fluid

studies, the diagnosis should be confirmed by analysis of the TH gene

itself. This is done via a blood sample and results can take some time.

There are again specific guidelines for blood sampling/shipping and

adherence is critical to the accurate diagnosis of TH Deficiency. For

information on how to collect and where to send the samples, or to receive

a testing packet please refer to the above information. If possible

samples should be collected from all family members.

Note: If abnormalities of neurotransmitter metabolites are displayed

in the Stage 1 testing procedure but are not conclusive to TH

Deficiency, then consideration should be given to other Pediatric

Neurotransmitter Diseases.


How is TH Deficiency treated?


Presently, the most well established treatment of TH Deficiency is

medication to help restore normal dopamine levels. Dopamine itself

cannot cross the blood-brain barrier directly and so it is necessary to

treat with a compound called L-Dopa in combination with another medication

called carbidopa. Sinemet is a commercially available medication

which contains both carbidopa and L-dopa together in a single tablet.

However, Sinemet was designed to treat adults with Parkinson’s disease

and the available dosages are much too high for many infants and young

children with TH Deficiency. It is imperative that the pharmacist compound

special doses of L-dopa and carbidopa for children.  Children with the TH Deficiency can experience excessive movement or irritability with low doses of L-dopa and extreme irritability, sleeplessness, and vomiting or persistent abnormal movements with excessive doses.


It is important to work closely with the physician to maximize the results

of medications and reduce side effects.


In children who are severely affected, less than one year of age, or prove intolerant of low dose L-dopa therapy, additional medications may be beneficial. They include:

Anticholinergic Agents - Artane

Monoamine Oxidase B Inhibitors - Selegeline

Serotonergic Medications

Gastrointestinal Medications

Miscellaneous category


Physical and occupational therapy is recommended. Speech therapy

has also been effective in some children


Medical advancements made in gene therapy or stem cell transplantation

may someday provide an avenue to cure the disorder.



Selected References:


For a complete list of articles on TH Deficiency, please refer to the Online

Mendelian Inheritance in Man  (OMIM) which is linked below. Before

clicking, you will need to enter the following information at the OMIM site:

Tyrosine Hydroxylase Deficiency

Key Words: “Tyrosine Hydroxylase”

Access Listing: 191290


Or for a complete list of up to date references contact the PND Association

PDF/Printable Guide to Tyrosine Hydroxylase (TH) deficiency